Quaternary Analogue Research Articles

On the molecular mechanism of nonspecific antimicrobial action of protonated diallylammonium polymers on mycobacterial cells

The protonated diallylammonium polymers (PDAA) are known to possess a high antimicrobial activity relative to a broad scope of pathogens, unlike their quaternary analog poly(N, N-diallyl-N, N-dimethylammonium chloride) (PDADMAC). Moreover, PDAA exhibits nonspecific antimicrobial activity relative to Mycobacterium tuberculosis, in contrast to known quaternary polymeric and low-molecular-weight biocides. The present paper is devoted to studying, using several physicochemical methods, the different facets of the interaction of secondary poly (diallylammonium trifluoroacetate) (PDAATFA) with Mycobacterium smegmatis – the nearest fast-growing relative of M. tuberculosis in comparison with the action of PDADMAC. We studied the interaction between polymer and phenolic glycolipids molecules (PGL) (i.e., molecules of the outer leaflet of both M. smegmatis and M. tuberculosis cell wall) by FTIR. We used phenyl-β-D-glucuronide as a model compound whose structure is close to that of the glycosylated phenolic part of the PGL molecule. It was assessed the polymer effect on transmembrane potential (TM) and permeability barrier of M. smegmatis. It was studied the biocidal activity of the polymers relative to M. smegmatis. The cytotoxic effect of PDAATFA on M. smegmatis cells was analyzed by TEM. We have proved the direct interaction of polymers with the outer membrane molecules for the first time. FTIR and the rest data show a formation of the non-covalent intermolecular hydrogen-bonded complex between protonated PDAATFA polymers and phenolic glycolipids that leads to the destruction of the mycobacterial outer membrane and, as a result, cell death. We believe that because of the structural similarity of cell wall chemistry and organization, this conclusion is proper for model organism M. smegmatis and pathogenic M. tuberculosis. Contrary to expected, the action of more hydrophobic PDADMAC does not lead to a destruction of the outer membrane but to a gradual suppression of the TM potential and cell death due to inhibition of general bioenergetic processes over the extended treatment time.

The Paleogene Gosau Group Slope Basins of the Incipient Eastern Alpine Orogenic Wedge: A Case Study at the Gams Basin (Austria)

This study investigates the Paleogene deep-water depositional system of the Gosau Group at Gams, Styria (Austria). The examined sections of the Danian to the Ypresian age (NP1–NP12) comprise sediments of the Nierental and Zwieselalm Formations. Four deep-water clastic facies assemblages were encountered: (1) pelagic marls with thin turbidites, (2) carbonate-rich turbidites, (3) carbonate-poor turbidites, and (4) marl-bearing turbidites; slump beds and mass flow deposits are common features in all facies assemblages. Based on heavy mineral, thin section, microprobe, and paleoflow analyses, provenance was from the surrounding Northern Calcareous Alps (NCA) rocks and exhuming metamorphic Upper Austroalpine units to the south. In addition, biogenic calcareous material was delivered by adjacent contemporaneous shelf zones. The sedimentary depocenter was situated at the slope of the incipient Alpine orogenic wedge, in frontal parts of the NCA, facing the subducting Penninic Ocean/Alpine Tethys. The evolution of the Gams Basin was connected to the eoalpine and mesoalpine orogeny and the adjunctive transpressional setting. The Gams deep-water depositional system is interpreted as an aggrading or prograding submarine fan, deposited into a small confined slope basin, positioned along an active continental margin, bound and influenced by (strike-slip) faults, related to crustal shortening. The development of the Gams slope basin and its infilling sequences was mainly dominated by tectonism and sediment supply, rather than by eustatic sea-level fluctuations. The basin was cut off during the Eocene due to renewed orogeny. A Quaternary analogue for the Upper Cretaceous to Paleogene basin setting of the Gams area is represented by the Santa Monica Basin in the California Continental Borderland.

A note on Assmus–Mattson type theorems

In the present paper, we give Assmus–Mattson type theorems for codes and lattices. We show that a binary doubly even self-dual code of length 24m with minimum weight 4m provides a combinatorial 1-design and an even unimodular lattice of rank 24m with minimum norm 2m provides a spherical 3-design. We remark that some of such codes and lattices give t-designs for higher t. As a corollary, we give some restrictions on the weight enumerators of binary doubly even self-dual codes of length 24m with minimum weight 4m. Ternary and quaternary analogues are also given.

The depositional signature of cyclic steps: A late Quaternary analogue compared to modern active delta slopes

AbstractCyclic‐step bedforms typifying a Froude‐supercritical flow regime are a recurrent component of depositional/erosional turbiditic systems. Over modern delta slopes, cyclic steps have been inferred from observations of upslope‐migrating crescent‐shaped bedforms. However, the recognition in the sedimentary record of the resulting stratal pattern and depositional facies remains challenging. In this study, the depositional facies observed in exposed late Quaternary glaciofluvial upper delta‐slope sands (Portneuf‐Forestville, Québec) are compared to those cored from a modern analogue consisting of sediment waves interpreted as cyclic steps (Southwind Fjord, Baffin Island). The fossil and modern delta slopes share similar context, morphology and stratigraphic record. The clinoform foresets dip 2 to 6° and consist of prevailing sand‐sized material including subhorizontal to upslope‐dipping top‐cut‐out turbidites. Individually, the latter are 5 to 20 cm thick and massive to planar laminated (prevailing TA and TB subdivisions). In the fossil delta slope, related successions form relatively thick, well‐bedded suites, which are truncated downcurrent by, and onlap upstreamward on, inclined composite erosion surfaces here referred to as pseudo‐foresets. Pseudo‐foresets are regularly spaced (10 to 30 m) and have dips greater than the clinoform foresets (ca 20°). Large composite scours form pseudo‐channel structures filled in by structureless pebbly sand deformed by sheared flame structures, in association with coarse sand showing undulating lamination and rip‐up clasts. Similar depositional facies are observed on the modern delta slope. The stratal pattern is best compatible with upslope‐migrating bedforms and structureless sand indicates hydraulic jump deposits typical of cyclic steps. Cyclic‐step flow events, encompassing a succession of genetically linked erosional cyclic steps, depositional cyclic steps and subsequent waning‐flow conditions, were associated with the dense basal layer of high‐density (stratified) turbidity currents. They are specifically associated with pseudo‐channel incision and infill. The deposition of well‐bedded suites on the stoss side, occasionally also on the lee side, is interpreted to result from a different type of turbidity current, which decelerated over the bedform stoss and accelerated over the lee sides of pre‐existing cyclic‐step morphologies. Antidunal flow conditions in expanded (non‐stratified) turbidity currents are tentatively suggested, deposition being linked, in this case, to interactions between inherited bedform morphologies and a near‐bed tractive layer. In the resulting dual flow model, the bulk of delta‐slope sands was mainly deposited from turbidity currents not developing a cyclic‐step instability, yet cyclic steps were instrumental in shaping and/or re‐organizing the delta‐slope morphology, bedforms and resulting stratal patterns. In some delta systems, the upslope migration of supercritical crescentic bedforms may not only be due to repetitive cyclic steps but could also result from antidunal turbidity current conditions remobilizing an inherited cyclically‐stepped morphology.

Late Cretaceous plateau deserts in the South China Block, and Quaternary analogues; sedimentology, dune reconstruction and wind-water interactions

Plateau deserts are among those continental systems with the most significant examples of clastic deposits associated with the complex combination of the action of ice, wind and water. The Late Cretaceous rocks of China contain the record of desert systems migration and partial destruction in a palaeoplateau desert. The evolution of the South China Block during Late Cretaceous was characterized by widespread destructive plate margin activity, this favoured orogenic uplift and high-altitude mountain ranges of which a direct consequence was a widespread rain shadow effect, triggering desertification and erg expansion similar to that of Quaternary counterparts in the Tibetan Plateau. This work presents a detailed analysis of the sedimentology, stratigraphic architecture, palaeogeography and palaeocurrent reconstruction of aeolian and associated alluvial depositional systems. The reconstruction of aeolian bedforms based on field-data analysis indicates that, during Late Cretaceous, draas and crescentic dunes accumulated and migrated in extensive intermontane desert systems. Heavy rains led to partial destruction of aeolian dunes and the reworking of aeolian sands in interdraa corridors. The fault-controlled subsidence and an increasing input of windblown sediments favoured the long-lasting accumulation of the erg system. Possible monsoonal rains recharged the groundwater system causing the rise of the regional phreatic level that favoured the ulterior long-lasting preservation of the aeolian system in the Xinjiang Basin. The dimensions and processes inferred from this Cretaceous desert system are similar to those observed today in the linking zone of the Taklamakan-Gobi Deserts, where meltwater flows from alpine glaciers in surrounding mountain ranges recharge the alluvial and fluvial network of the erg margin. The occurrence of striated cobbles in the alluvial facies suggests glacial activity in the catchment areas of the Cretaceous plateau.

U1.33T4Al8Si2 (T = Ni, Co): Complex Uranium Silicides Grown from Aluminum/Gallium Flux Mixtures.

Two new quaternary analogs of the Gd1+xFe4Si10-y structure type were grown from the reaction of uranium, silicon, and a transition metal (nickel or cobalt) in an excess of aluminum/gallium flux. The use of a mixed flux was found to be necessary for the formation of U1.33T4Al8Si2 (T = Ni, Co). Single crystal X-ray diffraction data shows the presence of disordered U/Si layers that are characteristic of this structure type; precession photographs indicate partial formation of a superstructure and stacking disorder along the c-axis. This disorder may be the cause of the spin glass behavior that is particularly evident in the nickel analog, which exhibits a spin freezing transition at TF = 7 K. These compounds are resistant to chemical attack and oxidation and may be potential waste forms.

Late Quaternary sediments on the carbonate platform off western India: Analogues of ancient platform carbonates

The Late Quaternary carbonate sediments and sedimentary rocks from the platform off western India were reviewed for their genesis and relationship with their ancient counter parts. Sub-marine cemented and vadose diagenetic limestones were recovered at different locations on the platform and, neomorphic limestones and caliche pisolites were recovered on the continental shelf south of the platform. Dolomites on the platform were primary and formed by microbial processes under hypersaline, sulphate-reducing conditions during the lowered sea levels. Aragonite ooids were formed from the mineralization of microbial filaments that enveloped their cortex portions. Phosphorites were found in organic-rich, aragonite muds on the continental slope adjacent to the platform and formed from the microbial mineralization of organic matter and replacement of carbonate by apatite during early diagenesis. Microbial processes thus played an important role in the formation of dolomites, ooids and phosphorites reported here and those in ancient deposits. Halimeda bioherms on the platform were grown luxuriantly from the nutrients brought by upwelling currents during the Late Pleistocene–Early Holocene sea level transgression and are similar to the Holocene–Recent deposits in the Indo-Pacific region. Lime muds were bio-detrital and formed primarily from the disintegration of Halimeda bioherms and carbonate skeletal on the platform and then exported to the slope. They resemble fine-grained limestones abundantly reported in ancient platforms. Thus, the different carbonate components on the platform are genetically related to their ancient ones and serve as Late Quaternary analogues for the ancient platform carbonates.

Protonated member of poly(diallylammonium) family: Hydrodynamic and conformational properties

Secondary polyamine in protonated salt form – poly(diallylammonium trifluoro-acetate) is characterized as representative of polymer series based on N,N-diallyl-ammonium. Its hydrodynamic behavior in 1 M NaCl has been compared with the other series members – quaternary poly(diallyldimethylammonium chloride) and tertiary poly(diallylmethylammonium trifluoroacetate). It was shown that these polymers belong to semirigid class whose Kuhn segment length ∼4 nm just slightly depends on chemical structure at high ionic strength. As specific for secondary polyamine, the sensitivity to proton equilibrium in solution and counter ion type was detected resulting in great difference of its Mark–Kuhn–Houwink equations from the quaternary analogue at the same conditions.

Dronedarone Modulates M1 and M3 Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. Amiodarone's most striking effect is to enhance the maximal response elicited by muscarinic agonists at the M₁, M₃, and M₅ receptors. Furthermore, the quaternary analog N-ethylamiodarone (NEA) is inhibitory at these receptors and appears to compete with amiodarone at that allosteric site. In the present studies, we show that dronedarone also modulates Gq-mediated responses at M₁ and M₃, although in a more discriminating manner. For example, dronedarone markedly enhances pilocarpine-stimulated release of arachidonic acid from CHO cells, via the M₃ receptor subtype, but does not affect the acetylcholine-stimulated response. Such probe-dependent effects are diagnostic of an allosteric interaction. In comparison to these effects at M₃, dronedarone is strongly inhibitory toward both pilocarpine and acetylcholine at the M₁ subtype. The effects of dronedarone are consistent with an interaction at the amiodarone site: dronedarone inhibits the enhancement of acetylcholine's response produced by amiodarone at the M₃ subtype; also, NEA reverses the enhancement of pilocarpine's response at M₃ produced by either dronedarone or amiodarone. In studies with the M₁-selective allosteric agonist 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC-260584), amiodarone enhanced the maximal response observed, whereas dronedarone was inhibitory. On the other hand, benzyl quinolone carboxylic acid, the well-known allosteric ligand that dramatically enhances the potency of acetylcholine at the M₁ subtype, had no effect on the response profile of AC-260584. In summary, dronedarone acts at M₁ and M₃ muscarinic receptors in a manner that complements amiodarone and provides an additional tool with which to investigate this novel allosteric site.

Highstand shelf fans: The role of buoyancy reversal in the deposition of a new type of shelf sand body

Although sea-level highstands are typically associated with sediment-starved continental shelves, high sea level does not hinder major river floods. Turbidity currents generated by plunging of sediment-laden rivers at the fluvial-marine interface, known as hyperpycnal flows, allow for cross-shelf transport of suspended sand beyond the coastline. Hyperpycnal flows in southern California have deposited six subaqueous fans on the shelf of the northern Santa Barbara Channel in the Holocene. Using eight cores and nine grab samples, we describe the deposits, age, and stratigraphic architecture of two fans in the Santa Barbara Channel. Fan lobes have up to 3 m of relief and are composed of multiple hyperpycnite beds ∼5 cm to 40 cm thick. Deposit architecture and geometry suggest the hyperpycnal flows became positively buoyant and lifted off the seabed, resulting in well-sorted, structureless, elongate sand lobes. Contrary to conventional sequence stratigraphic models, the presence of these features on the continental shelf suggests that active-margin shelves may locally develop high-quality reservoir sand bodies during sea-level highstands, and that such shelves need not be solely the site of sediment bypass. These deposits may provide a Quaternary analogue to many well-sorted sand bodies in the rock record that are interpreted as turbidites but lack typical Bouma-type features.

Discovery of a marine-derived bis-indole alkaloid fascaplysin, as a new class of potent P-glycoprotein inducer and establishment of its structure–activity relationship

The screening of IIIM natural products repository for P-gp modulatory activity in P-gp over-expressing human adenocarcinoma LS-180 cells led to the identification of 7 natural products viz. withaferin, podophyllotoxin, 3-demethylcolchicine, agnuside, reserpine, seseberecine and fascaplysin as P-gp inducers. Fascaplysin (6a), a marine-derived bis-indole alkaloid, was the most potent among all of them, showing induction of P-gp with EC50 value of 25 nM. P-gp induction is one of the recently targeted strategy to increase amyloid-β clearance from Alzheimer brains. Thus, we pursued a medicinal chemistry of fascaplysin to establish its structure–activity relationship for P-gp induction activity. Four series of analogs viz. substituted quaternary fascaplysin analogs, D-ring opened quaternary analogs, D-ring opened non-quaternary analogs, and β-carbolinium analogs were synthesized and screened for P-gp induction activity. Among the total of 48 analogs screened, only quaternary nitrogen containing analogs 6a–g and 10a, 10h–l displayed promising P-gp induction activity; whereas non-planar non-quaternary analogs 9a–m, 13a–n, 15a–h were devoid of this activity. The P-gp induction activity of best compounds was then confirmed by western-blot analysis, which indicated that fascaplysin (6a) along with 4,5-difluoro analog of fascaplysin 6f and D-ring opened analog 10j displayed 4–8 fold increase in P-gp expression in LS-180 cells at 1 μM. Additionally, compounds 6a and 6f also showed inhibition of acetylcholinestease (AChE), an enzyme responsible for neuronal loss in Alzheimer's disease. Thus, fascaplysin and its analogs showing promising P-gp induction along with AChE inhibition at 1 μM, with good safety window (LS-180: IC50 > 10 μM, hGF: 4 μM), clearly indicates their promise for development as an anti-Alzheimer agent.

From T2,2@Bmmim to Alkali@T2,2@Bmmim Ivory Ball-like Clusters: Ionothermal Syntheses, Precise Doping, and Photocatalytic Properties.

Presented here are the syntheses, structures, and properties of an In-Sn-Se compound based on a ternary super-supertetrahedral T2,2 cluster nested by Bmmim cations and two of its alkali-doped quaternary analogues. By means of a one-pot ionothermal method, an alkali metal ion (Cs(+) or Rb(+)) could be precisely doped into the central cavity of the cluster, forming an alkali@T2,2@Bmmim quaternary cluster. Remarkably, the undoped compound exhibited excellent stability and visible light photodegradation ability over a wide range of pH, especially in acidic conditions.

Non-classical mechanism of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor channel block by fluoxetine.

Antidepressants have many targets in the central nervous system. A growing body of data demonstrates the influence of antidepressants on glutamatergic neurotransmission. In the present work, we studied the inhibition of native Ca(2+)-permeable and Ca(2+)-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rat brain neurons by fluoxetine. The Ca(2+)-impermeable AMPA receptors in CA1 hippocampal pyramidal neurons were weakly affected. The IC50 value for the inhibition of Ca(2+)-permeable AMPA receptors in giant striatal interneurons was 43 ± 7 μM. The inhibition of Ca(2+)-permeable AMPA receptors was voltage dependent, suggesting deep binding in the pore. However, the use dependence of fluoxetine action differed markedly from that of classical AMPA receptor open-channel blockers. Moreover, fluoxetine did not compete with other channel blockers. In contrast to fluoxetine, its membrane-impermeant quaternary analog demonstrated all of the features of channel inhibition typical for open-channel blockers. It is suggested that fluoxetine reaches the binding site through a hydrophobic access pathway. Such a mechanism of block is described for ligands of sodium and calcium channels, but was never found in AMPA receptors. Molecular modeling suggests binding of fluoxetine in the subunit interface; analogous binding was proposed for local anesthetics in closed sodium channels and for benzothiazepines in calcium channels.

P.5.a.002 Association of plasma C-reactive protein levels with mild cognitive impairment and Alzheimer's disease

Radiolabeled analogues of 3-quinuclidinyl benzilate (QNB) localize in the myocardium by virtue of ligand-receptor interactions. The radioiodinated derivative exhibits less favorable non-receptor interactions than tritiated QNB in the myocardium, probably due to increased lipophilicity. In order to prevent intracellular localization and partitioning into lipid membranes, we prepared the N-methyl quaternary analogue of the iodinated derivative [125I]3-quinuclidinyl 4-iodobenzilate. In vitro and in vivo results indicate that the quaternization reduces the affinity of the analogue to a value too low for advantageous receptor-mediated localization.

Further characterization of the allosteric site of action of amiodarone at Gq‐linked muscarinic receptors (LB616)

We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. Amiodarone’s most striking effect is to enhance the maximal response elicited by muscarinic agonists at the M1, M3, and M5 receptors. Furthermore, the quaternary analog N‐ethylamiodarone (NEA) is inhibitory at these receptors and appears to compete with amiodarone at that allosteric site. In the present studies, we show that dronedarone (DRON) also modulates Gq‐mediated responses, although in a more discriminating manner. For example, DRON markedly enhances pilocarpine‐stimulated release of arachidonic acid from CHO cells, via the M3 receptor subtype, but does not affect the acetylcholine‐stimulated response. In comparison to these effects at M3, DRON is strongly inhibitory toward both pilocarpine and acetylcholine at the M1 subtype. The effects of DRON are consistent with an interaction at the amiodarone site: DRON inhibits the enhancement of acetylcholine’s response produced by amiodarone at the M3 subtype; and, NEA reverses the enhancement of pilocarpine’s response at M3 produced by either DRON or amiodarone. In studies with the M1‐selective allosteric agonist AC260584, amiodarone enhanced the maximal response observed, whereas DRON was inhibitory. On the other hand, BQCA, the well‐known PAM that dramatically enhances the potency of acetylcholine at the M1 subtype, had no effect on the response profile of AC260584. In summary, DRON acts at Gq‐linked muscarinic receptors in a manner that complements amiodarone and provides an additional tool with which to investigate this novel allosteric site.Grant Funding Source: Supported by PHS R01 005214 to JE

Late Quaternary stratigraphy, sedimentology and geochemistry of an underfilled lake basin in the Puna plateau (northwest Argentina)

AbstractDepositional models of ancient lakes in thin‐skinned retroarc foreland basins rarely benefit from appropriate Quaternary analogues. To address this, we present new stratigraphic, sedimentological and geochemical analyses of four radiocarbon‐dated sediment cores from the Pozuelos Basin (PB; northwest Argentina) that capture the evolution of this low‐accommodation Puna basin over the past ca. 43 cal kyr. Strata from the PB are interpreted as accumulations of a highly variable, underfilled lake system represented by lake‐plain/littoral, profundal, palustrine, saline lake and playa facies associations. The vertical stacking of facies is asymmetric, with transgressive and thin organic‐rich highstand deposits underlying thicker, organic‐poor regressive deposits. The major controls on depositional architecture and basin palaeogeography are tectonics and climate. Accommodation space was derived from piggyback basin‐forming flexural subsidence and Miocene‐Quaternary normal faulting associated with incorporation of the basin into the Andean hinterland. Sediment and water supply was modulated by variability in the South American summer monsoon, and perennial lake deposits correlate in time with several well‐known late Pleistocene wet periods on the Altiplano/Puna plateau. Our results shed new light on lake expansion–contraction dynamics in the PB in particular and provide a deeper understanding of Puna basin lakes in general.

Discriminative‐stimulus effects of 3,4‐methylenedioxy‐N‐methylamphetamine (MDMA) and a novel MDMA quatenary analog

MDMA (ecstasy), popularized as a “club drug,” is a psychoactive and abused substance. It is often assumed that the behavioral effects of MDMA are due to central actions, though this has not been tested. Using a quaternary analog of MDMA (qMDMA) we tested that assumption by training male Sprague‐Dawley rats (n = 6) to discriminate intraperitoneal (i.p.) injections of 1.7 mg/kg of MDMA HCl from saline in a two‐lever discrimination procedure. When MDMA was administered before daily sessions, responses on one of two keys intermittently produced food presentation; responses on the alternate key produced occasional food deliveries after saline injections. MDMA produced dose‐related increases in the percentage of responses on the drug‐appropriate key with an ED50 value of 0.56 mg/kg. In addition the serotonin releaser fenfluramine (i.p.), as well as p.o. MDMA produced dose‐dependent substitution for MDMA. Neither morphine (i.p.) nor qMDMA (i.p.) substituted for MDMA across a range of doses from those having no effect to those decreasing response rates. When MDMA and qMDMA were administered via intraventricular cannulae, full substitution was obtained at 300 μg of MDMA immediately after infusion and partial substitution (~75%) was obtained with the quaternary compound at 250 μg when subjects were tested one hr after infusion. These results validate qMDMA as a tool for investigating central vs. peripheral actions of MDMA.

Mixing and Mass Transfer in Multicontact Miscible Displacements

In this work, we investigate the accuracy of some physical models that are frequently used to describe and interpret dispersive mixing and mass transfer in compositional reservoir simulation. We have designed a quaternary analog fluid system (alcohol–water–hydrocarbon) that mimics the phase behavior of CO2-hydrocarbon mixtures at high pressure and temperature. A porous medium was designed using PolyTetraFlouroEthylene (PTFE) materials to ensure that the analog oil acts as the wetting phase, and the properties of the porous medium were characterized in terms of porosity, permeability and dispersivity. Relative permeability and interfacial tension (IFT) measurements were also performed to delineate interactions between the fluid system and the porous medium. The effluent concentrations from two-component first-contact miscible (FCM) displacement experiments exhibit a tailing behavior that is attributed to imperfect sweep of the porous medium: A feature that is not captured by normal dispersion models. To represent this behavior in displacement calculations, we use dual-porosity (DP) models including mass transfer between flowing and stagnant porosities. Two 4-component two-phase displacement experiments were performed at near-miscible and multicontact miscible (MCM) conditions and the effluent concentrations were interpreted by numerical calculations. We demonstrate that the accuracy of our displacement calculations relative to the experimental observations is sensitive to the selected models for dispersive mixing, mass transfer between flowing and stagnant porosities, and IFT scaling of relative permeability functions. We also demonstrate that numerical calculations substantially agree with the experimental observations for some physical models with limited need for model parameter adjustment. The combined experimental and modeling effort presented in this work identifies and explores the impact of a set of physical mechanisms (dispersion and mass transfer) that must be upscaled adequately for field-scale displacement calculations in DP systems.

Differential modulation of rNaV1.4 channel inactivated states by lidocaine and its charged analogue QX222

Background The local anesthetic lidocaine is generally believed to reach its binding site in the intracellular vestibule of the voltage-gated sodium channel via the cell membrane. QX222 is a permanently charged, quaternary amine analogue of lidocaine, which can access this binding site via a hydrophilic route across the channel protein. The mutation I1575E of the adult rat muscle-type sodium channel (rNaV1.4) opens such a hydrophilic pathway. When bound to the internal vestibule, 500 μM lidocaine stabilize both fast and slow inactivated states. We have tested if QX222, once bound to the internal vestibule of I1575E mutant channel, exerts a similar modulatory action on inactivated states as lidocaine.

Tissue cholinesterase inhibition by propranolol and related drugs.

The effect of (+/-)-propranolol and some related drugs have been investigated on the cholinesterase (ChE) enzyme activity of heart and brain tissues of the rat. Brain homogenates hydrolysed more methacholine than benzoylcholine and the reverse was true for the heart tissue. In-vitro, (+/-)-, (+)- and (-)-propranolol, as well as its quaternary analogue, UM-272, all significantly inhibited heart and brain ChE. Timolol and sotalol, however, were less potent. In-vivo, (+/-)-propranolol (30 mumol kg-1) significantly inhibited brain ChE activity in rats when compared with saline controls. It is inferred that propranolol inhibits brain and heart ChE enzyme in a non-stereoselective manner and that this cholinomimetic action could be involved in the mediation of some of its therapeutic effects.